S1
Supporting Information
for
Flow carbonylation of sterically hindered ortho-substituted
iodoarenes
Carl J. Mallia,1 Gary C. Walter
2 and Ian R. Baxendale*
1
Address: 1
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE,
United Kingdom and 2Syngenta CP R&D Chemistry, Jealott's Hill International Research
Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
Email: Ian R. Baxendale - [email protected]
*Corresponding author
Experimental part
Unless specified, reagents were obtained from commercial sources and used without further
purification. Solvents were obtained from Fisher scientific, and H2O was deionised before
use.
NMR spectra were recorded on either Bruker Avance-400, Varian VNMRS-600 or Varian
VNMRS-700 instrument and was calibrated to the residual solvent according to the
literature.1 Assignments are based on DEPT-135, COSY, NOESY, HSQC and HMBC
spectra.
Liquid chromatography-mass spectrometry (LCMS) was performed on an Agilent HP 1100
series chromatograph (Mercury Luna 3µ C18 (2) column) attached to a Waters ZQ2000 mass
spectrometer with ESCi ionisation source in ESI mode. Elution was carried out at a flow rate
of 0.6 mL/min using a reverse phase gradient of MeCN–water containing 0.1% formic acid.
Gradient = 0–1 min: hold MeCN 5%, 1–4 min: ramp MeCN 5–95%, 4–5 min: hold MeCN
95%, 5–7 min: ramp MeCN 95–5%, 7–8 min: hold MeCN 5%. Retention times are reported
as Rt. High resolution mass spectra (HRMS) were recorded on a Waters Micromass LCT
Premier spectrometer using time of flight with positive electrospray ionisation (ESI+), an
ABI/MDS Sciex Q-STAR Pulsar with ESI+ and an ASAP (atmospheric pressure solids
analysis probe ionisation), or a Bruker BioApex II 4.7e FTICR utilising either ESI+ or a
positive electron ionisation (EI+) source equipped with a direct insertion probe. The mass
reported is that containing the most abundant isotopes (35
Cl and 79
Br). Limit: ± 5 ppm.
S2
IR spectra were recorded neat on a Perkin-Elmer Spectrum Two FT-IR spectrometer using
Universal ATR sampling accessories. Letters in parentheses refer to the relative absorbency
of the peak: w – weak (<40% of the most intense peak), m – medium (40–75% of the most
intense peak), s – strong (>75% of the most intense peak) and br – broad.
Melting points were recorded on an Optimelt automated melting point system with a heating
rate of 1 °C/min (70% onset point and 10° clear point) and are uncorrected.
X-ray diffraction experiment was carried out on a D8 Venture 3-circle Bruker AXS
diffractometer with a PHOTON 100 CMOS area detector, using graphite-monochromated
Mo K radiation ( = 0.71073 Å) from IS microsource and a Cryostream (Oxford
Cryosystems) open-flow N2 cryostat. The structure was solved by direct methods (SHELXS
2013/1 software2) and refined by full-matrix least squares against F
2 of all reflections, using
OLEX23 and SHELXL 2014/7 software.
4 Crystallographic data for structure 29 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
CCDC-1470506.
S3
General procedures:
Ortho-substituted carbonylation in flow using a “tube-in-tube” reactor.
For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec
Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set
at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back
pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady
state after which time the flow streams were switched to pass from the loops where the
substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of
palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of
1,4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-
substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol)
and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane.
An Omnifit®
column filled with 1.71 cm3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned
just before the back pressure regulator to trap any particulate matter formed to avoid blocking
of the back pressure regulator. After the substrates were passed through the system, the outlet
of the flow stream was directed into a receptacle where the excess carbon monoxide gas was
vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl
acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a
separating funnel. After collecting the aqueous layer, the organic layer was extracted with
sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by
the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL).
The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to
give the crude product as a solid. The crude product was then recrystallised from the
appropriate solvent.
Heck-carbonylation in flow using the plug flow reactor.
For the Heck-carbonylation of iodobenzene and ethanol, a mixture of 1.64 mL DBU (11.0
mmol) and 5 mL of ethanol was made to which palladium acetate (5 mg, 0.022 mmol) was
added and left stirring for 15 minutes to obtain a pale orange solution. Iodo benzene (2.05 g,
10.0 mmol) was then added to this solution and left stirring for 5 minutes. This solution was
then injected in the flow reactor (Uniqsis FlowSyn), at the following conditions: coil
temperature of 120 °C, carbon monoxide rate of 2 mL/min at 8 bar of pressure (supplied
using EL-Flow Select Bronkhorst flow meter), solvent flow rate of 0.3 mL/min, 100 psi BPR
S4
and a residence time of 2 hours. The crude was purified on a silica column (9:1, hexane: ethyl
acetate) to obtain 0.6 g (41% isolated yield) as a pale yellow oil.
Note: The flow reactor was equilibrated at the appropriate conditions for 2 h prior to the
addition of the substrates. Additionally, by using a flow of 2 mL/min of carbon monoxide it
was ensured that equal size plugs (~0.5 cm long) of gas/liquid were obtained allowing for
large interfacial areas, which should ensure carbon monoxide saturation in the liquid plug
over the 2 h residence time.
Ortho-substituted carbonylation in batch (Conventional Lab).
A solution of palladium acetate (20 mg, 0.08 mmol) and triphenylphosphine (48 mg, 0.168
mmol) in 11.8 mL of 1,4-dioxane was prepared, to which 2-chloro-iodobenzene (0.401g, 1.68
mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) were
added in a N2 filled 25 mL flask. A balloon (made from two balloons inside each other) of
carbon monoxide was attached to the flask and the flask was emptied through an empty
needed. This process was repeated once and then the third time the carbon monoxide in the
balloon was not emptied by removing the empty needle. The reaction was heated to reflux,
cooled after 2 h or 24 h, solvent evaporated and the same extraction/purification for the flow
protocol was repeated using acetonitrile to recrystallise the product.
Ortho-substituted carbonylation in batch (High-Pressure Lab).
A solution of palladium acetate (80 mg, 0.32 mmol) and triphenylphosphine (192 mg, 0.672
mmol) in 24 mL of 1,4-dioxane was prepared and stirred for 15 min, to which a solution of 2-
chloro-iodobenzene (1.602 g, 6.72 mmol), triethylamine (1.088 g, 1.50 mL, 10.76 mmol) and
water (2.02 g, 112 mmol) in 24 mL of 1,4-dioxane was added in the Parr autoclave (stainless
steel, 100 mL capacity, 200 bar maximum pressure). The autoclave was tightly sealed and
placed in the heating rig. The autoclave was then purged with nitrogen (3 × 10 bar) and with
carbon monoxide (3 × 10 bar), keeping 10 bar of carbon monoxide in the autoclave at which
point it was heated to 110 °C over 15 minutes. The carbon monoxide pressure was adjusted to
15 bar and the reaction was left stirring for 2 h and was then cooled down to 30 °C over 2 h.
The autoclave was then purged with nitrogen (4 × 10 bar) and the reaction mixture removed
from the autoclave. The same extraction/purification sequence as for the flow protocol was
repeated.
S5
Spectroscopic data for products:
2-Chlorobenzoic acid, [CAS Number: 118-91-2], 4:
Isolated yield: 0.183 g (90%, 1.30 mmol scale), pale yellow crystals (recrystallised from
MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.42 (s, br, 1H), 7.78 (d, J = 7.6 Hz, 1H),
7.68 – 7.17 (m, 3H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 167.2 (C), 133.0 (CH), 132.0
(C), 131.9 (C), 131.2 (CH), 131.1 (CH), 127.7 (CH); IR (neat) ν = 1683 (s, C=O) cm-1
; LC-
MS (MeCN), Rt. 2.34 min, m/z = 157.0 [M+H]+. HR-MS (ESI-TOF) calculated for
C7H6O2Cl 157.0056, found 157.0063 (Δ = 4.5 ppm). M.p. 140-141 °C (MeCN) (Literature:
139-140 °C).5
2-Bromobenzoic acid, [CAS Number: 88-65-3], 10:
Isolated yield: 0.185 g (70%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.39 (s, br, 1H), 7.78 – 7.66 (m, 2H), 7.50 – 7.40 (m,
2H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 167.4 (C), 133.7 (CH), 132.5 (CH), 130.6
(CH), 127.7 (CH), 127.5 (C), 119.9 (C); IR (neat) ν = 1675 (s, C=O) cm-1
; LC-MS (MeCN),
Rt. 2.27 min, m/z = 200.8 [M+H]+. HR-MS (
+ESI-TOF) calculated for C7H6O2Br 200.9551,
found 200.9554 (Δ = 1.49 ppm). M.p. 147-149 °C (MeCN) (Literature: 147-149 °C).5
2-Fluorobenzoic acid, [CAS Number: 445-29-4], 11:
Isolated yield: 0.152 g (84%, 1.30 mmol scale), yellow crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.23 (s, br, 1H), 7.87 (td, J = 7.6, 1.7 Hz, 1H), 7.64
(dddd, J = 7.9, 6.9, 5.0, 1.9 Hz, 1H), 7.35 – 7.26 (m, 2H); 13
C NMR (151 MHz, DMSO- d6)
δ/ppm 165.5 (d, J = 3.0 Hz, C), 161.5 (d, J = 256.7 Hz, C), 135.1 (d, J = 8.9 Hz, CH), 132.3
S6
(CH), 124.9 (d, J = 3.8 Hz, CH), 119.8 (d, J = 10.3 Hz, C), 117.4 (d, J = 22.1 Hz, CH); 19
F
NMR (376 MHz, DMSO-d6) δ/ppm -110.65 (s); IR (neat) ν = 1685 (s, C=O) cm-1
; LC-MS
(MeCN), Rt. 2.06 min, m/z = 139.1 [M-H]-. HR-MS (
-ESI-TOF) calculated for C7H4O2F
139.0195, found 139.0189 (Δ = 4.3 ppm). M.p. 122-124 °C (MeCN) (Literature: 123-125
°C).6
2-(Trifluoromethyl)benzoic acid, [CAS Number: 433-97-6], 12:
Isolated yield: 0. 0.176g (71%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, CDCL3) δ/ppm 11.23 (s, br, 1H), 8.05 – 7.97 (m, 1H), 7.86 – 7.78 (m,
1H), 7.73 – 7.63 (m, 2H); 13
C NMR (151 MHz, CDCl3) δ/ppm 172.2 (C), 132.4 (CH), 132.0
(CH), 131.3 (CH), 129.7 (q, J = 2.7 Hz, C), 129.7 (q, J = 49.2 Hz, C), 127.2 (q, J = 8.5 Hz,
CH), 123.3 (q, J = 410.3 Hz, C); 19
F NMR (376 MHz, DMSO-d6) δ/ppm -59.32 (s); IR (neat)
ν = 1700 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.47 min, m/z = 189.4 [M-H]-. HR-MS (
-ESI-
TOF) calculated for C8H5F3O2 189.0163, found 189.0171 (Δ = 4.2 ppm). M.p. 108-109 °C
(MeCN) (Literature: 108-110 °C).7
2-Methoxybenzoic acid, [CAS Number: 579-75-9], 13:
Isolated yield: 0.125 g (63%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz,CDCl3) δ/ppm 10.76 (s, br, 1H), 8.18 (dd, J = 7.8, 1.8 Hz, 1H), 7.58
(ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.14 (td, J = 7.6, 1.0 Hz, 1H), 7.06 (dd, J = 8.4, 1.1 Hz, 1H),
4.08 (s, 3H); 13
C NMR (151 MHz, CDCl3) δ/ppm 165.6 (C), 158.2 (C), 135.2 (CH), 133.9
(CH), 122.3 (CH), 117.7 (C), 111.7 (CH), 56.8 (CH3); IR (neat) ν = 1668 (s, C=O) cm-1
; LC-
MS (MeCN), Rt. 2.03 min, m/z = 153.3 [M+H]+. HR-MS (
+ESI-TOF) calculated for C8H9O3
153.0552, found 153.0554 (Δ = 1.3 ppm). M.p. 101-102 °C (MeCN) (Literature: 100-102
°C).8
S7
2-Methylbenzoic acid, [CAS Number: 118-90-1], 14:
Isolated yield: 0.106 g (60%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, CDCl3) δ/ppm 11.65 (s, br, 1H), 8.13 – 8.05 (m, 1H), 7.47 (td, J = 7.5,
1.5 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 2.68 (s, 3H); 13
C NMR (151 MHz, CDCl3) δ/ppm 173.6
(C). 141.5 (C), 133.1 (CH), 132.1 (CH), 131.7 (CH), 128.4 (C), 126.0 (CH), 22.3 (CH3); IR
(neat) ν = 1679 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.58 min, m/z = 135.4 [M-H]-. HR-MS (
-
ESI-TOF) calculated for C8H7O3 135.0446, found 135.0448 (Δ = 1.5 ppm). M.p. 103-104 °C
(MeCN) (Literature: 104-105 °C).8
2-chloronicotinic acid, [CAS Number: 2942-59-8], 15:
Isolated yield: 0.116 g (57%, 1.30 mmol scale), yellow crystals (recrystallised from EtOH); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.78 (s, br, 1H), 8.56 (dd, J = 4.8, 2.0 Hz, 1H), 8.23
(dd, J = 7.7, 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 4.8 Hz, 1H); 13
C NMR (151 MHz, DMSO- d6)
δ/ppm 165.8 (C), 151.7 (CH), 147.8 (C), 140.0 (CH), 128.2 (C), 123.2 (CH); IR (neat) ν =
1701 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 1.79 min, m/z = 156.0 [M-H]-. HR-MS (
-ESI-TOF)
calculated for C6H3NO2Cl 155.9852, found 155.9848 (Δ = 2.6 ppm). M.p. 183 °C (EtOH,
decomposed) (Literature: 190-192 °C).9
4-bromo-2-chlorobenzoic acid, [CAS Number: 59748-90-2], 16:
Isolated yield: 0.232 g (76%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.55 (s, br, 1H) 7.86 (d, J = 1.9 Hz, 1H), 7.75 (d, J =
8.3 Hz, 1H), 7.66 (dd, J = 8.3, 1.9 Hz, 1H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 165.9
(C), 133.0 (C), 132.9 (CH), 132.5 (CH), 130.5 (C), 130.4 (CH), 125.1 (C); IR (neat) ν = 1676
(s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.56 min, m/z = 232.9 [M-H]-. HR-MS (
-ESI-TOF)
S8
calculated for C7H3O2ClBr 232.9005, found 232.9013 (Δ = 3.43 ppm). M.p. 171-172°C
(MeCN) (Literature: 170-172 °C).10
2-chloro-4-(trifluoromethyl)benzoic acid, [CAS Number: 23228-45-7], 17:
Isolated yield: 0.128 g (44%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.85 (s, br, 1H), 8.01 – 7.94 (m, 2H), 7.82 (dd, J =
8.3, 1.7 Hz, 1H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 165.9 (s, C), 135.8 (s, CH), 132.16
(q, J = 32.3 Hz, C), 132.15 (s, C), 131.4 (s, C), 127.4 (q, J = 3.8 Hz, CH), 124.2 (q, J = 3.8,
3.0 Hz, CH), 121.6 (s, C); 19
F NMR (376 MHz, DMSO-d6) δ/ppm -61.62 (s); IR (neat) ν =
1685 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.68 min, m/z = 223.0 [M-H]-. HR-MS (
-ESI-TOF)
calculated for C8H3O2F3Cl 222.9774, found 222.9778 (Δ = 1.8 ppm). M.p. 114-115°C
(MeCN) (Literature: 114-116 °C).9
2-Chloro-4-methylbenzoic acid, [CAS Number: 7697-25-8], 18:
Isolated yield: 0.152 g (69%, 1.30 mmol scale), grey crystals (recrystallised from MeCN); 1H
NMR (400 MHz, DMSO-d6) δ/ppm 13.19 (s, br, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.38 (dd, J =
1.7, 0.9 Hz, 1H), 7.24 (ddd, J = 7.9, 1.7, 0.8 Hz, 1H), 2.34 (s, 3H); 13
C NMR (151 MHz,
DMSO- d6) δ/ppm 166.5 (C), 143.3 (C), 131.9 (C), 131.1 (CH), 131.0 (CH), 128.1 (C), 127.8
(CH), 20.5 (CH3); IR (neat) ν = 1675 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.41 min, m/z =
171.3[M+H]+. HR-MS (
+ESI-TOF) calculated for C8H8O2Cl 171.0213, found 171.0207 (Δ =
3.5 ppm). M.p. 155-156 °C (MeCN) (Literature: 150-152 °C).11
S9
2-Chloro-4-fluorobenzoic acid, [CAS Number: 2252-51-9], 19:
Isolated yield: 0.154 g (89%, 1.30 mmol scale) or 2.372 g (85%, 16.00 mmol scale), white
crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.45 (s, br,
1H), 7.91 (dd, J = 8.7, 6.3 Hz, 1H), 7.56 (dd, J = 9.0, 2.6 Hz, 1H), 7.32 (ddd, J = 8.8, 8.2, 2.6
Hz, 1H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 165.7 (s, C), 163.2 (d, J = 252.6 Hz, C),
133.7 (d, J = 11.1 Hz, C), 133.3 (d, J = 9.8 Hz, CH), 127.7 (d, J = 3.5 Hz, C), 118.1 (d, J =
25.2 Hz, CH), 114.60 (d, J = 21.4 Hz, CH); 19
F NMR (376 MHz, DMSO-d6) δ/ppm -106.76
(s); IR (neat) ν = 1670 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.31 min, m/z = 173.1 [M-H]-.
HR-MS (-ESI-TOF) calculated for C7H3O2FCl 172.9806, found 172.9810 (Δ = 2.3 ppm).
M.p. 185-186 °C (MeCN) (Literature: 180-181 °C).12
2,4-dichlorobenzoic acid, [CAS Number: 50-84-0], 20:
Isolated yield: 0.171 g (69%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.56 (s, br, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.74 (d, J
= 2.1 Hz, 1H), 7.53 (dd, J = 8.4, 2.1 Hz, 1H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 165.8
(C), 136.5 (C), 133.0 (C), 132.4 (CH), 130.2(CH), 130.1 (C), 127.5 (CH); IR (neat) ν = 1691
(s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.85 min, m/z = 189.0 [M-H]-. HR-MS (
-ESI-TOF)
calculated for C7H3O2Cl2 188.9510, found 188.9512 (Δ = 1.1 ppm). M.p. 162-163 °C
(MeCN) (Literature: 162 °C).13
2,5-dichlorobenzoic acid, [CAS Number: 50-79-3], 21:
Isolated yield: 0.118 g (48%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.73 (s, br, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.66 – 7.54
S10
(m, 2H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 165.5 (C), 133.2 (C), 132.34 (CH), 132.25
(CH), 131.8 (C), 130.3 (C), 130.2 (CH); IR (neat) ν = 1675 (s, C=O) cm-1
; LC-MS (MeCN),
Rt. 2.52 min, m/z = 189.0 [M-H]-. HR-MS (
-ESI-TOF) calculated for C7H3O2Cl2 188.9510,
found 188.9518 (Δ = 4.2 ppm). M.p. 153-155 °C (MeCN) (Literature: 155-156 °C).14
2-chloro-5-(trifluoromethyl)benzoic acid, [CAS Number: 657-06-7], 22:
Isolated yield: 0.136 g (47%, 1.30 mmol scale), white crystals (recrystallised from CHCl3); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.92 (s, br, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.91 (dd, J
= 8.5, 2.3 Hz, 1H), 7.83 – 7.78 (m, 1H); 13
C NMR (101 MHz, DMSO- d6) δ/ppm 166.0 (C),
136.4 (d, J = 1.3 Hz, C), 133.2 (C), 132.4 (CH), 129.4 (q, J = 3.4 Hz, CH), 128.3 (q, J = 33.1
Hz, C), 127.9 (q, J = 3.8 Hz, CH), 123.9 (q, J = 273.5 Hz, C); 19
F NMR (376 MHz, DMSO-
d6) δ/ppm -61.34 (s); IR (neat) ν = 1690 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 2.99 min, m/z =
223.0 [M-H]-. HR-MS (
-ESI-TOF) calculated for C8H3O2F3Cl 222.9774, found 222.9766 (Δ
= 3.6 ppm). M.p. 81-83 °C (CHCl3) (Literature: 91-93 °C).9
2-bromo-5-formylbenzoic acid, [CAS Number: 1289007-84-6], 23:
Isolated yield: 0.127 g (43%, 1.30 mmol scale), amorphous solid; 1H NMR (400 MHz,
DMSO-d6) δ/ppm 13.70 (s, br, 1H), 10.03 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.98 – 7.86 (m,
2H); 13
C NMR (101 MHz, DMSO- d6) δ/ppm 192.0 (CH), 166.6 (C), 135.2 (C), 135.0 (CH),
134.5 (C), 132.0 (CH), 131.5 (CH), 126.7 (C); IR (neat) ν = 1663 (s, C=O), 1731 (s, C=O)
cm-1
; LC-MS (MeCN), Rt. 2.05 min, m/z = 227.0 [M-H]-. HR-MS (
-ESI-TOF) calculated for
C8H4BrO3 226.9344, found 226.9352 (Δ = 3.5 ppm).
2-fluoro-5-formylbenzoic acid, [CAS Number: 550363-85-4], 24:
Isolated yield: 0.102 g (47%, 1.30 mmol scale), yellow crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 13.66 (s, br, 1H), 10.04 (s, 1H), 8.43 (dd, J = 7.2, 2.3
S11
Hz, 1H), 8.17 (ddd, J = 8.5, 4.7, 2.3 Hz, 1H), 7.56 (dd, J = 10.6, 8.5 Hz, 1H); 13
C NMR (151
MHz, DMSO- d6) δ/ppm 191.8 (s, CH), 164.8 (d, J = 266.0 Hz, C), 164.5 (d, J = 3.1 Hz, C),
135.5 (d, J = 10.9 Hz, CH), 134.5 (d, J = 2.7 Hz, CH), 133.1 (d, J = 3.1 Hz, C), 120.6 (d, J =
11.3 Hz, C), 118.7 (d, J = 23.6 Hz, CH); 19
F NMR (376 MHz, DMSO-d6) δ/ppm -101.25 (s);
IR (neat) ν = 1701 (s, C=O), 1685 (s, C=O) cm-1
; LC-MS (MeCN), Rt. 1.93 min, m/z = 167.1
[M-H]-. HR-MS (
-ESI-TOF) calculated for C8H4FO3 167.0144, found 167.0146 (Δ = 1.2
ppm). M.p. 162 °C (MeCN, decomposed).
2-Bromo-5-(ethoxymethyl)benzoic acid, 25:
Isolated yield: 0.156 g (36%, 1.00 mmol scale), amorphous solid; 1H NMR (400 MHz,
CDCl3) δ/ppm 10.40 (s, br, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.38 (dd, J
= 8.2, 2.2 Hz, 1H), 4.51 (s, 2H), 3.57 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1, 3H); 13
C NMR (101
MHz, CDCl3) δ/ppm 170.9 (C), 138.4 (C), 135.0 (CH), 132.7 (CH), 131.5 (CH), 130.5 (C),
121.5 (C), 71.4 (CH2), 66.3 (CH2), 15.3 (CH3); IR (neat) ν = 1699 (s, C=O) cm-1
; LC-MS
(MeCN), Rt. 2.15 min, m/z = 259.3 [M+H]+. HR-MS (
+ESI-TOF) calculated for C10H12BrO3
258.9970, found 258.9965 (Δ = 1.9 ppm).
(rac)-(2-bromo-5-((2R,3S,5S)-3-(tert-butoxycarbonyl)-5-(ethoxycarbonyl)-3-methyl-1-
pivaloylpyrrolidin-2-yl)benzoic acid, 26:
Isolated yield: 0.366 g (54%, 1.76 mmol scale), colourless crystals (recrystallised from
hexane/EtOAc); 1H NMR (700 MHz, CDCl3) δ/ppm 10.02 (s, br, 1H), 8.14 (s, 1H), 8.11 –
8.00 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 5.09 (s, 1H), 4.55 (dd, J = 12.0, 7.1 Hz, 1H), 4.29 (qd,
J = 7.1, 1.7 Hz, 2H), 2.49 (t, J = 12.7 Hz, 1H), 1.99 (dd, J = 13.2, 7.1 Hz, 1H), 1.46 (s, 3H),
1.33 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H), 1.07 (s, 9H). 13
C NMR (176 MHz, CDCl3) δ/ppm 178.9
(C), 172.4 (C), 170.8 (C), 170.2 (C), 139.8 (C), 135.1 (CH), 133.5 (CH), 132.7 (CH), 130.1
(C), 122.0 (C), 82.3 (C), 69.7 (CH), 61.5 (CH2), 61.2 (CH), 56.3 (C), 39.7 (C), 32.8 (CH2),
28.4 (CH3), 27.7 (CH3), 23.7 (CH3), 14.3 (CH3); IR (neat) ν = 1723 (s, C=O), 1627 (m, amide
I band) cm-1
; LC-MS (MeCN), Rt. 3.30 min, m/z = 540.5 [M+H]+. HR-MS (
+ESI-TOF)
S12
calculated for C25H24BrNO7 540.1597, found 540.1582 (Δ = 2.8 ppm), M.p. 162-165 °C
(hexane/EtOAc).
2,6-dimethoxybenzoic acid, [CAS Number: 1466-76-8], 27:
Isolated yield: 0.042 g (16%, 1.30 mmol scale), white crystals (recrystallised from MeCN); 1H NMR (400 MHz, DMSO-d6) δ/ppm 12.72 (s, br, 1H), 7.32 (t, J = 8.4 Hz, 1H), 6.69 (d, J =
8.4 Hz, 2H), 3.76 (s, 6H); 13
C NMR (151 MHz, DMSO- d6) δ/ppm 167.2 (C), 156.6 (C),
130.9 (CH), 114.8 (C), 104.6 (CH), 56.2 (CH3); IR (neat) ν = 1695 (s, C=O) cm-1
; LC-MS
(MeCN), Rt. 2.07 min, m/z = 181.1 [M-H]-. HR-MS (
-ESI-TOF) calculated for C9H9O4
181.0501, found 181.0508 (Δ = 3.9 ppm). M.p. 184-187 °C (MeCN) (Literature: 185-187
°C).15
(4-Bromo-3-iodophenyl)methanol, 30:
To a suspension of 4-bromo-3-iodobenzaldehyde (1.24 g, 4.0 mmol) in methanol (6 mL) at 0
ºC, NaBH4 (0.08 g, 2.0 mmol) was added in small portions over 10 minutes. The reaction
mixture was allowed to warm to room temperature and left stirring for 1 h. The solvent of the
reaction mixture was then evaporated under vacuum and the residue was dissolved in ethyl
acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was dried
over sodium sulphate and the solvent evaporated under vacuum to give the desired product as
white solid which was used without further purification.
Isolated yield: 1.17 g (93%, 4.00 mmol scale), white crystals (recrystallised from CHCl3); 1H
NMR (400 MHz, CDCl3) δ/ppm δ 7.85 – 7.81 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H),
7.17 – 7.12 (dd, J = 4.0, 8.0 Hz 1H), 4.56 (s, 2H), 2.35 (s, br, 1H); 13
C NMR (101 MHz,
CDCl3) δ/ppm 141.5 (C), 138.6 (CH), 132.7 (CH), 128.7 (C), 128.0 (CH), 101.4 (C), 63.3
(CH2); IR (neat) ν = 3293 (br, C-OH), 2921 (w), 1450 (m), 1387 (m), 1195 (w), 1101 (m),
1006 (s), 808 (s) cm-1
; LC-MS (MeCN), Rt. 2.14 min, m/z = 295.14 [M-H2O]+. HR-MS
(+ESI-TOF) calculated for C7H5BrI 294.8619, found 294.8625 (Δ = 2.0 ppm). M.p. 44-47 °C
(CHCl3).
S13
1-Bromo-4-(ethoxymethyl)-2-iodobenzene, 31:
To a solution of (4-bromo-3-iodophenyl)methanol (30) (1.15 g, 3.67 mmol) in THF (4 mL),
NaH (60% in hexane, 0.224 g, 5.5 mmol) was added in small portions over 5 minutes while
keeping the reaction mixture at 0 ºC. Iodoethane (0.860 g, 0.44 mL, 5.5 mmol) was then
added to the reaction mixture which was then allowed to warm up to room temperature and
left stirring for 2 h. The solvent of the reaction mixture was then evaporated under vacuum
and the residue was dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25
mL). The organic layer was dried over sodium sulphate and the solvent evaporated under
vacuum to give the desired product as yellow oil which was purified using flash silica
chromatography 0.5:9.5 – 2:3 EtOAc/hexane gradient to give the product as a colourless
liquid.
Isolated yield: 0.698 g (56%, 3.67 mmol scale), colourless liquid, Rf: 0.32 (2/8,
EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ/ppm 7.87 (dt, J = 1.9, 0.7 Hz, 1H), 7.60 (d, J
= 8.2 Hz, 1H), 7.20 (ddt, J = 8.2, 2.0, 0.7 Hz, 1H), 4.43 (d, J = 0.8 Hz, 2H), 3.56 (q, J = 7.0
Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H); 13
C NMR (101 MHz, CDCl3) δ/ppm 139.5 (C), 139.2 (CH),
132.5 (CH), 128.6 (CH), 128.5 (C), 101.1 (C), 71.0 (CH2), 66.1 (CH2), 15.2 (CH3); IR (neat)
ν = 2974 (w), 2865 (w), 1454 (m), 1383 (m), 1100 (s), 1009 (m), 811 (m) cm-1
; GC-MS
(MeCN), Rt. 4.72 min, m/z = 340.0 [M]+. LC-MS (MeCN), Rt. 4.31 min, m/z = 294.86 [M-
EtOH]+
, HR-MS (+ESI-TOF) calculated for C7H5BrI 294.8619, found 294.8611 (Δ = 2.7
ppm), ASAP (MeCN), Rt. 0.51 min, m/z = 335.9 [M+EtOH+MeCN]+. HR-MS (
+AP-TOF)
calculated for C9H8BrIN 335.8885, found 335.8875 (Δ = 3.0 ppm), ASAP (MeCN), Rt. 0.51
min, m/z = 381.9 [M+H+MeCN]+. HR-MS (
+AP-TOF) calculated for C11H14BrINO
381.9304, found 335.9297 (Δ = 1.8 ppm).
(rac)-(2S,4S,5R)-4-tert-butyl 2-ethyl 5-(4-bromo-3-iodophenyl)-4-methylpyrrolidine-2,4-
dicarboxylate, 32:
To a suspension of 4-bromo-3-iodobenzaldehyde (1.24 g, 4.0 mmol) and glycine
hydrochloride (0.838 g, 6.0 mmol) in acetonitrile (6 mL), triethylamine (0.836 g, 6.0 mmol)
S14
was added and reaction mixture was left stirring at room temperature for 4 h. The solvent of
the reaction mixture was then evaporated under vacuum and the residue was dissolved in
ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic layer was
dried over sodium sulphate and the solvent evaporated under vacuum to give the desired
imine intermediate which was used in the next step without further purification. The imine
intermediate was dissolved in THF (6 mL) and tert-butyl methacrylate (1.138 g, 8.0 mmol)
was added followed by lithium bromide (0.694 g, 8.0 mmol) and triethylamine (1.11 g, 8.0
mmol). The reaction mixture was left stirring at room temperature for 2 h after which the
solvent of the reaction mixture was then evaporated under vacuum and the residue was
dissolved in ethyl acetate (25 mL) and washed with brine solution (3 x 25 mL). The organic
layer was dried over sodium sulphate and the solvent evaporated under vacuum to give the
desired crude product as a yellow oil which was purified using flash silica chromatography
1:9 EtOAc/hexane.
Isolated yield: 2.00 g (93%, 4.0 mmol scale), yellow oil, Rf: 0.15 (2/8, EtOAc/hexane); 1H
NMR (600 MHz, CDCl3) δ/ppm; 7.83 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.22 (dd,
J = 8.3, 2.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.98 – 3.92 (m, 2H), 2.73 (s, br, 1H), 2.60 (dd,
J = 13.2, 8.9 Hz, 1H), 2.04 (dd, J = 13.2, 8.1 Hz, 1H), 1.42 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H),
1.12 (s, 9H). 13
C NMR (151 MHz, CDCl3) δ/ppm 173.6 (C), 173.0 (C), 141.5 (C), 139.3
(CH), 132.2 (CH), 128.6 (CH), 128.5 (C), 100.9 (C), 81.2 (C), 71.4 (CH), 61.3 (CH2), 58.8
(CH), 55.1 (C), 41.3 (CH2), 27.7 (CH3), 24.4 (CH3), 14.4 (CH3); IR (neat) ν = 2997 (w), 1933
(w), 1717 (s, C=O), 1449 (m), 1367 (m), 1248 (s), 1149 (s), 1110 (s), 1033 (m), 1009 (m),
847 (m) cm-1
; LC-MS (MeCN), Rt. 3.77 min, m/z = 538.4 [M+H]+. HR-MS (
+ESI-TOF)
calculated for C19H25BrINO4 538.0090, found 538.0073 (Δ = 3.2 ppm).
(rac)-(2S,4S,5R)-4-tert-butyl 2-ethyl 5-(4-bromo-3-iodophenyl)-1-ethyl-4-
methylpyrrolidine-2,4-dicarboxylate, 29:
To a solution 32 (2.0 g, 3.72 mmol) in dichloromethane (4 mL), pivolyl chloride (0.580 g,
0.594 mL, 4.83 mmol) was added followed by triethylamine (0.489 g, 0.674 mL, 4.83 mmol)
and reaction was left stirring at room temperature for 2 h. The reaction mixture was then
washed with brine solution (3 x 25 mL) and the organic layer dried over sodium sulphate and
the solvent evaporated under vacuum to give the desired product as a yellow oil which was
purified using flash silica chromatography 1:9 EtOAc/hexane.
Isolated yield: 1.49 g (65%, 3.72 mmol scale), white crystals (recrystallised from CH3Cl), Rf:
0.24 (2/8, EtOAc/hexane); 1H NMR (600 MHz, CDCl3) δ/ppm 8.04 (s, 1H), 7.83 (d, J = 8.3
Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 4.95 (s, 1H), 4.50 (dd, J = 12.0, 7.1 Hz, 1H), 4.29 (q, J =
7.1 Hz, 2H), 2.46 (t, J = 12.6 Hz, 1H), 1.96 (dd, J = 13.1, 7.1 Hz, 1H), 1.42 (s, 3H), 1.33 (t, J
= 7.1 Hz, 3H), 1.22 (s, 9H), 1.07 (s, 9H); 13
C NMR (151 MHz, CDCl3) δ/ppm δ 178.5 (C),
S15
172.2 (C), 170.5 (C), 140.8 (C), 140.1 (CH), 132.4 (CH), 129.5 (CH), 129.0 (C), 100.7 (C),
82.1 (C), 69.0 (CH), 61.2 (CH2), 60.9 (CH), 56.1 (C), 39.5 (C), 32.6 (CH2), 28.3 (CH3), 27.7
(CH3), 23.5 (CH3), 14.2 (CH3); IR (neat) ν = 2975 (w), 2935 (w), 1743 (s, C=O), 1722 (s,
C=O), 1632 (s, amide I band), 1456 (m), 1394 (m), 1251 (m), 1197 (s), 1167 (s), 1129 (s),
730 (s) cm-1
; LC-MS (MeCN), Rt. 4.05 min, m/z = 622.5 [M+H]+. HR-MS (
+ESI-TOF)
calculated for C21H29BrINO4 622.0665, found 622.0662 (Δ = 0.5 ppm).
Crystal data: 29, C24H33BrINO5, M=622.32, T=120 K, triclinic, space group P 1 (No. 2),
a=8.8223(5), b=9.7894(5), c= 17.1881(9) Å, α= 94.479(2), β= 101.255(2), γ= 116.252(2)º,
V= 1282.7(1) Å3, Z=2, Dc=1.611 g cm
–3, μ=0.74 mm
–1, 34192 reflections with 2θ≤71.7º,
10848 unique, Rint=0.031, R(F)=0.027 [9096 data with I≥2σ(I)], wR(F2)=0.059 (all data).
CCDC-1470506.
S16
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